In this study, we introduce -substituted iminothiolane (NIT) as a robust protecting group for lysine side chains. NIT is compatible with Fmoc-SPPS and can be efficiently removed under mild nucleophilic conditions. Notably, NIT offers enhanced hydrophilicity compared to traditional orthogonal lysine-protecting groups and does not undergo intramolecular migration.
View Article and Find Full Text PDFIn the fast-evolving landscape of targeted cancer therapies, the revolutionary class of biotherapeutics known as antibody-drug conjugates (ADCs) are taking center stage. Most clinically approved ADCs utilize cleavable linkers to temporarily attach potent cytotoxic payloads to antibodies, allowing selective payload release under tumor-specific conditions. In this study, we explored the utilization of 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), a cyclic β-diketone featuring an active alkylidene group, to develop a novel chemically labile linker.
View Article and Find Full Text PDFThe synthesis of linker-payloads is a critical step in developing antibody-drug conjugates (ADCs), a rapidly advancing therapeutic approach in oncology. The conventional method for synthesizing cathepsin B-labile dipeptide linkers, which are commonly used in ADC development, involves the solution-phase assembly of cathepsin B-sensitive dipeptides, followed by the installation of self-immolative -aminobenzyl carbonate to facilitate the attachment of potent cytotoxic payloads. However, this approach is often low yield and laborious, especially when extending the peptide chain with components like glutamic acid to improve mouse serum stability or charged amino acids or poly(ethylene glycol) moieties to enhance linker hydrophilicity.
View Article and Find Full Text PDFA photoinitiated thiol-ene "click" reaction was used to synthesize -lipidated collagen model peptide amphiphiles. Use of 2-iminothiolane provided an epimerization-free thiol handle required for thiol-ene based incorporation of lipid moieties onto collagen-based peptide sequences. This approach not only led to improvements in the triple helical characteristics of the resulting collagen model peptides but also increased the aqueous solubility of the peptide amphiphiles.
View Article and Find Full Text PDFRuthenium piano-stool complexes have been explored for their anticancer activity and some promising compounds have been reported. Herein, we conjugated a derivative of plecstatin-1 to peptides in order to increase their cancer cell targeting ability. For this purpose, plecstatin-1 was modified at the arene ligand to introduce a functional amine handle (), which resulted in a compound that showed similar activity in an anticancer activity assay.
View Article and Find Full Text PDFOver the last few decades, design and discovery of chemical reactions that enable modification of proteins at pre-determined sites have been the focus of synthetic organic chemists. As an invaluable tool, the site-and chemoselective functionalization of peptides and proteins offers an exciting opportunity for creating high-value multicomponent conjugates with diverse applications in life sciences and pharmacology. In recent years, multiple strategies have emerged that target natural amino acids directly or convert them into other reactive species for further ligations.
View Article and Find Full Text PDFPancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation.
View Article and Find Full Text PDFHerein we report the first examples of thiol-selective heterobifunctional electrophiles, -vinyl acrylamides, that enable efficient highly selective thiol-thiol bioconjugations and cysteine modification of peptides. We demonstrate that these new classes of thiol-selective scaffolds can readily undergo a thia-Michael addition and an orthogonal radical induced thiol-ene "click" reaction under biocompatible conditions. Furthermore, the formation of an unexpected Markovnikov ,-acetal hydrothiolation was explained using computational studies.
View Article and Find Full Text PDFThe large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market 'boom', garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification of a suitable combination of antibody, linker, and payload, as of September 2021, 11 ADCs have been granted FDA approval, with eight of these approved since 2017 alone. Optimism for this therapeutic approach is clear, despite the COVID-19 pandemic, 2020 was a landmark year for deals and partnerships in the ADC arena, suggesting that there remains significant interest from Big Pharma.
View Article and Find Full Text PDFWe herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel "CLipP"ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.
View Article and Find Full Text PDFIn this work we report the synthesis of mono lipidated peptides containing a 3-mercaptopropionate linker in the N-terminus by means of a photoinitiated thiol-ene reaction (S-lipidation). We evaluate the self-assembling and hydrogelation properties of a library of mono S-lipidated peptides containing lipid chains of various lengths and demonstrate that hydrogelation was driven by a balance between the lipid chain's hydrophobicity and the peptide's facial hydrophobicity. We further postulate that a simple calculation using estimated values of log D could be used as a predictor of hydrogelation when designing similar systems.
View Article and Find Full Text PDFWhile the global market for peptide/protein-based therapeutics is witnessing significant growth, the development of peptide drugs remains challenging due to their low oral bioavailability, poor membrane permeability, and reduced metabolic stability. However, a toolbox of chemical approaches has been explored for peptide modification to overcome these obstacles. In recent years, there has been a revival of interest in photoinduced radical thiol-ene chemistry as a powerful tool for the construction of therapeutic peptides.
View Article and Find Full Text PDFHerein is described the introduction of lipid moieties onto a simplified teixobactin pharmacophore using a modified Cysteine Lipidation on a Peptide or Amino acid (CLipPA) technique, whereby cysteine was substituted for 3-mercaptopropionic acid (3-MPA). A truncated teixobactin analog was prepared with the requisite thiol handle, thus enabling an array of vinyl esters to be conveniently conjugated onto the simplified teixobactin pharmacophore to yield -lipidated cyclic lipopeptides.
View Article and Find Full Text PDFThe effect of installing different lipid chains (C, C, C, and C) on the N-terminus of an octapeptide derived from the antiparallel β-interface of the diaminopimelate decarboxylase protein homotetramer has been investigated. Notably, the C peptide conjugate assembled into wide twisted nanoribbons and formed hydrogels, which to the best of our knowledge constitutes the first example of a peptide containing an eight carbon alkyl chain that demonstrates these properties, a space typically occupied by peptide amphiphiles with long lipid chains. Furthermore, this self-assembling lipopeptide exhibited pH and temperature stability with shear thinning properties suitable for biomedical applications.
View Article and Find Full Text PDFCulicinin D (1), a 10 amino acid peptaibol containing several unusual residues, has been shown to exhibit potent anticancer activity. Previous work in our group towards developing a structure-activity relationship (SAR) for this peptaibol has concentrated on replacement of the synthetically challenging AHMOD (3) and AMD (4) residues, resulting in the discovery of analogues with equivalent or better potency and simplified synthesis. The SAR of this peptaibol is extended in this work by investigating the effect of the N-terminal lipid tail and C-terminal amino alcohol, revealing the key contribution of each of these moieties on antiproliferative activity in a panel of breast and lung cancer cell lines.
View Article and Find Full Text PDFIncreased water solubility and long-range intermolecular ordering have been introduced into the fluorescent organic molecule thiophene-diketopyrrolopyrrole (TDPP) via its conjugation to the octapeptide HEFISTAH, which is derived from the protein-protein β-interface of the homo-tetramer protein diaminopimelate decarboxylase. The octapeptide, and its TDPP mono- and cross-linked conjugates were synthesised using 9-fluorenylmethoxycarbonyl (Fmoc) based solid-phase peptide synthesis (SPPS). Unlike the unmodified peptide, the resulting mono-linked and cross-linked peptides showed a fibrous morphology and formed hydrogels at 4 wt% in water at neutral pH, but failed to assemble at pH 2 and pH 9.
View Article and Find Full Text PDFWe herein report the synthesis of analogues of the antimicrobial lipopeptide, paenipeptin C', by installing varying lipid moieties using thiol-ene CLipPA (Cysteine Lipidation on a Peptide or Amino Acid) chemistry. Biological evaluation against both Gram-negative and Gram-positive strains indicated that several analogues possessed potent broad-spectrum antimicrobial activity.
View Article and Find Full Text PDFCulicinin D (1), a 10 amino acid peptaibol originally isolated from Culicinomyces clavisporus, exhibits potent activity against a range of cancer cell lines. Building on our previous work exploring the structure-activity relationship (SAR) of the unusual (2S,4S,6R)-AHMOD residue, a series of analogues of culicinin D were prepared to further investigate the SAR of these peptaibols. Alanine scanning of a potent and readily accessible analogue 23 revealed the effect of each residue on antiproliferative activity, and a small panel of analogues were prepared to explore the SAR of the non-natural amino acid residue (2S,4R)-AMD.
View Article and Find Full Text PDFNaturally occurring cyclic lipopeptides exhibit a diverse range of biological activities and possess several favourable properties. Chemically synthesising and modifying these natural compounds can alter their biological and physical properties. Cyclic lipopeptides are often difficult to synthesise, especially when the lipid moiety is directly attached to the cyclic scaffold.
View Article and Find Full Text PDFAggregation of the pathological amyloid beta (Aβ) isoform Aβ into senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). The biochemical significance of this phenomenon therefore necessitates the need for ready access to Aβ for research purposes. Chemical synthesis of the peptide, however, is technically difficult to perform given its propensity to aggregate both on resin during solid phase peptide synthesis and in solution during characterization.
View Article and Find Full Text PDFCulicinin D is a 10 amino acid peptaibol containing a rare and synthetically challenging (2S,4S,6R)-AHMOD residue, that exhibits potent antiproliferative activity against MDA-MB-468 cells. An SAR study focusing on replacement of the AHMOD residue was undertaken, culminating in the revelation that a 6-hydroxy or 6-keto substituent was essential to retain potent low nanomolar antiproliferative activity.
View Article and Find Full Text PDFThe amyloidogenic Aβ42 peptide was efficiently prepared using a double linker system, markedly improving solubility and chromatographic peak resolution, thus enabling full characterisation using standard techniques. The tag was readily cleaved with sodium hydroxide and removed by aqueous extraction, affording Aβ42 in high purity and yield for biophysical characterisation studies.
View Article and Find Full Text PDFThere is an increasing demand for biocompatible materials in biomedical applications. Herein, we report a modified α-helical decapeptide segment from the cardiac troponin C, which self-assembles into fibers with a secondary β-sheet structure. These fibers cross-link via a novel supramolecular threading mechanism which results in an atypical stiff hydrogel (' ≈ 13 kPa).
View Article and Find Full Text PDFThe first total synthesis of the highly N-methylated acetylene-containing lipopeptide jahanyne, an apoptosis-inducing natural product from marine cyanobacteria, is reported. A late-stage solution-phase coupling enabled introduction of the C-terminal ketone pyrrolidine moiety. A modified Fmoc solid-phase synthesis strategy was adopted to effectively couple multiple sterically hindered N-methylated amino acids while suppressing epimerization.
View Article and Find Full Text PDFAdvanced lipid peroxidation end-products (ALEs) accumulate with ageing and oxidative stress-related diseases. Despite their potential therapeutic value, there are no suitably protected ALE building blocks reported in the literature to enable their site-specific incorporation into synthetic peptides. The synthesis of an Fmoc-protected ALE building block, N-(3-methylpyridinium)lysine (MP-lysine) and its incorporation into collagen model peptides is reported.
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